Modulation (particularly inhibition) of cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc Technol 2001 6, 1005-1024) is an attractive goal for development of small-molecule drugs. Anti-angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis, and rheumatoid arthritis. As well, cell antiproliferative agents are desirable to slow or stop the growth of tumors.
One such target for small-molecule modulation of antiangiogenic and antiproliferative activity is c-Met. The kinase c-Met, is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron and Sea. Expression of c-Met occurs in a wide variety of cell types including epithelial, endothelial, and mesenchymal cells where activation of the receptor induces cell migration, invasion, proliferation and other biological activities associated with “invasive cell growth.” As such, signal transduction through c-Met receptor activation is responsible for many of the characteristics of tumor cells.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide are two small molecule inhibitors of c-Met that are currently undergoing clinical investigation as treatments for a range of cancers. There is accordingly an ongoing need for new and efficient processes for making these two promising cancer therapies.